Affiliations: University of Pennsylvania Cancer Center
   Posting Date 

 

 

The University of Pennsylvania Medical Center has initiated a new trial for patients with malignant glioma. There is currently little to offer patients for whom standard treatment has failed. However, pre-clinical investigations have suggested that the transfer of a drug susceptibility gene into brain tumors may be possible and may result in the death of tumor cells. 

Previous gene therapy studies in glioma have used recombinant retroviruses as vectors. While still regarded as promising, this approach is inefficient in gene transfer, according to Stephen Eck, MD, PhD, of the University of Pennsylvania Institute for Human Gene Therapy (IHGT). As a result, investigators at IHGT have developed a replication defective adenovirus vector that is believed to be superior to prior gene therapy approaches. The adenovirus vector containing the herpes simplex thymidine kinase (HSV-tk) gene will be injected into brain tumors to confer sensitivity to ganciclovir. In the presence of HSV-tk, ganciclovir is converted to a toxic metabolite that will kill cells containing the HSV-tk gene (i.e., tumor cells) and neighboring cells. 

This study is being directed by Jane Alavi, MD, of the University of Pennsylvania Cancer Center and Dr. Eck, who is a co-program leader of the Cancer Center's Gene Therapy in Cancer Program. Kevin Judy, MD, an assistant professor of neurosurgery, will introduce the adenovirus by direct stereotactic injection into the brain tumor. The adenovirus vector has been engineered to be non-replicating; therefore, the virus is severely limited in its ability to disseminate to areas outside the brain. 

This phase I trial (UPCC 3394) has the following specific aims: (1) to determine the clinical and histological toxicity of intra-tumor injection of a recombinant adenovirus expressing HSV-tk, followed by intravenous ganciclovir, in patients with recurrent glioma, and (2) to assess the response of malignant gliomas to this treatment by brain imaging with volumetric MRI scans and positron emission tomography (PET) with 18F-fluorodeoxyglucose. 

All patients on the trial must have gliomas recurrent after radiation therapy, tumors accessible for stereotactic injections and good performance status. Previous brachytherapy or stereotactic radiosurgery are not permitted. Patients with small tumors are preferable. 

Half of the patients (those with unresectable lesions) will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. The other patients (those with tumors amenable to surgical debulking) will receive the same treatment, except their tumors will be surgically resected at day 7, and a second dose of virus will be injected into the residual, unresectable portion of the tumor. Intravenous ganciclovir will be continued for an additional 14 days. 

The subjects will be hospitalized in the Clinical Research Center -- a 10-bed, NIH-funded clinical research unit located at the Hospital of the University of Pennsylvania -- for two to three weeks. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. Tissue removed at the time of resection will be analyzed for evidence of adenovirus protein expression, HSV-tk DNA (by PCR), inflammation and tumor necrosis. The size and metabolic activity of the tumors after treatment will be assessed by volumetric MRI scans and PET scans. It is expected that this study will determine the safety of intracranially administered recombinant adenoviruses. It also will provide evidence for the efficacy of adenovirally administered HSV-tk, as well as valuable information for the development of future vectors. 

For more information, or to refer a patient, please call Jane Alavi,
MD, at 215-662-6319, or Stephen Eck, MD, PhD, at 215-898-4178.  You
also may call the Brain Tumor Center at 215-662-4485.